Bronchial asthma, a complex and heterogeneous trait, is a major public health problem, affecting nearly 10% of the general population, and disproportionately affecting children. Moreover, the prevalence of asthma has increased dramatically over the past three decades, an increase thought to be due to changes in our environment. These environmental changes include reductions in the incidence of infectious diseases that may exert protective effects against asthma, as suggested by the Hygiene Hypothesis1. While the infectious agents responsible for this relationship, and the precise mechanisms by which infectious microorganisms might protect against asthma are very poorly understood, epidemiological studies suggest that infection with bacteria (e.g., Helicobacter pylori (2,3), endotoxin (4), or Acinetobacter lwoffi (5) or viruses (e.g., hepatitis A virus (6,7)) can reduce the likelihood of developing asthma.
The role of viral infection in modulating the development of asthma is particularly complex, because many different viruses affect the respiratory tract, some appearing to enhance and some appearing to protect against the development of asthma. For example, infection with human rhinovirus in children before three years of age increases the later risk of developing asthma (8), while other respiratory viral infections appear to protect against the later development of asthma (9-14). However, in older individuals with established asthma, respiratory viral infection, particularly with rhinovirus and also with influenza A virus, almost always triggers acute symptoms of asthma (15-17). These discrepancies, without wishing to be bound or limited by theory, may be due to the timing of the infection, since infection in very young children may profoundly alter the developing innate immune system in such a way as to protect against the later development of asthma, or to the specific immunological cell types activated by a given infectious agent.
In asthma, a population of innate immune cells known as natural killer T (NKT) cells have been suggested to play a very important pathogenic role (20, 47). Some patients, particularly those with mild or well-controlled asthma, have few detectable pulmonary NKT cells, while patients with severe, poorly controlled asthma have a significant increase in pulmonary NKT cells (19, 48, 49). In many distinct mouse models of asthma, the presence of specific NKT cell subsets have been shown to be required for the development of airway hyperreactivity (AHR), a cardinal feature of asthma. For example, in an allergen-induced AHR model, CD4+IL-17RB+ NKT cells are required (19, 20, 50, 51); in an ozone-induced AHR model, an NK1.1−, IL-17 producing subset is required (21); and in a Sendai virus-induced AHR model, a CD4+ NKT cell population that interacts with alternatively activated alveolar macrophages is required (22).
Recent evidence indicates that NKT cells participate in immune responses to a growing list of infectious microorganisms. These immune responses can be driven either by direct TCR recognition of specific glycolipids expressed by microorganisms, as in the case of Borrelia burgdorferi (39) and Sphingomonas paucimobilis (32, 40), or by indirect responses to cytokines released by activated dendritic cells (DCs), as in the case of Salmonella typhimurium (41), E. coli, S. aureus and L. monocytogenes (42), and Mycobacteria tuberculosis (43, 44). Thus, NKT cells have been implicated both in enhancing protective immunity to a diverse group of pathogens, as well as in enhancing or causing pathogenic immune responses, such as those found in asthma or autoimmune disorders.